Environmental Pollutants and Metabolic Disorders: The Multi-Exposure Scenario of Life

Obesity and diabetes have reached epidemic proportions the past few decades and continue to progress worldwide with no clear sign of decline of the epidemic. Obesity is of high concern because it is the main risk factor for a number of non-communicable diseases such as cardiovascular diseases and type 2 diabetes. Metabolic diseases constitute a major challenge as they are associated with an overall reduced quality of life and impose a heavy economic burden on countries. These are multifactorial diseases and it is now recognized that environmental exposure to man-made chemical pollutants is part of the equation. Yet, risk assessment procedures are based on a one-by-one chemical evaluation which does not meet the specificities of the multi-exposure scenario of life, e.g., a combined and long-term exposure to even the smallest amounts of chemicals. Indeed, it is assumed that environmental exposure to chemicals will be negligible based on the low potency of each chemical and that they do not interact. Within this mini-review, strong evidences are brought that exposure to low levels of multiple chemicals especially those shown to interfere with hormonal action, the so-called endocrine disrupting compounds do trigger metabolic disturbances in conditions in which no effect was expected if considering the concentration of each individual chemical in the mixture. This is known as the cocktail effect. It means that risk assessment procedures are not protective enough and thus that it should be revisited for the sake of Public Health

Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency

Context: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia and/or overwhelming infection. Mutations of the ACTH receptor (MC2R) and the melanocortin 2 receptor accessory protein (MRAP), FGD types 1 and 2 respectively, account for approximately 45% of cases. Objective: A locus on chromosome 8 has previously been linked to the disease in three families, but no underlying gene defect has to date been identified. Design: The study design comprised single-nucleotide polymorphism genotyping and mutation detection. Setting: The study was conducted at secondary and tertiary referral centers. Patients: Eighty probands from families referred for investigation of the genetic cause of FGD participated in the study. Interventions: There were no interventions. Results: Analysis by single-nucleotide polymorphism array of the genotype of one individual with FGD previously linked to chromosome 8 revealed a large region of homozygosity encompassing the steroidogenic acute regulatory protein gene, STAR. We identified homozygous STAR mutations in this patient and his affected siblings. Screening of our total FGD patient cohort revealed homozygous STAR mutations in a further nine individuals from four other families. Conclusions: Mutations in STAR usually cause lipoid congenital adrenal hyperplasia, a disorder characterized by both gonadal and adrenal steroid deficiency. Our results demonstrate that certain mutations in STAR (R192C and the previously reported R188C) can present with a phenotype indistinguishable from that seen in FGD

Role of Hypothalamic Melanocortin System in Adaptation of Food Intake to Food Protein Increase in Mice

The hypothalamic melanocortin system—the melanocortin receptor of type 4 (MC4R) and its ligands: α-melanin-stimulating hormone (α-MSH, agonist, inducing hypophagia), and agouti-related protein (AgRP, antagonist, inducing hyperphagia)—is considered to play a central role in the control of food intake. We tested its implication in the mediation of the hunger-curbing effects of protein-enriched diets (PED) in mice. Whereas there was a 20% decrease in food intake in mice fed on the PED, compared to mice fed on an isocaloric starch-enriched diet, there was a paradoxical decrease in expression of the hypothalamic proopiomelanocortin gene, precursor of α-MSH, and increase in expression of the gene encoding AgRP. The hypophagia effect of PED took place in mice with invalidation of either MC4R or POMC, and was even strengthened in mice with ablation of the AgRP-expressing neurons. These data strongly suggest that the hypothalamic melanocortin system does not mediate the hunger-curbing effects induced by changes in the macronutrient composition of food. Rather, the role of this system might be to defend the body against the variations in food intake generated by the nutritional environment

Link between Intestinal CD36 Ligand Binding and Satiety Induced by a High Protein Diet in Mice

CD36 is a ubiquitous membrane glycoprotein that binds long-chain fatty acids. The presence of a functional CD36 is required for the induction of satiety by a lipid load and its role as a lipid receptor driving cellular signal has recently been demonstrated. Our project aimed to further explore the role of intestinal CD36 in the regulation of food intake. Duodenal infusions of vehicle or sulfo-N-succinimidyl-oleate (SSO) was performed prior to acute infusions of saline or Intralipid (IL) in mice. Infusion of minute quantities of IL induced a decrease in food intake (FI) compared to saline. Infusion of SSO had the same effect but no additive inhibitory effect was observed in presence of IL. No IL- or SSO-mediated satiety occurred in CD36-null mice. To determine whether the CD36-mediated hypophagic effect of lipids was maintained in animals fed a satietogen diet, mice were subjected to a High-Protein diet (HPD). Concomitantly with the satiety effect, a rise in intestinal CD36 gene expression was observed. No satiety effect occurred in CD36-null mice. HPD-fed WT mice showed a diminished FI compared to control mice, after saline duodenal infusion. But there was no further decrease after lipid infusion. The lipid-induced decrease in FI observed on control mice was accompanied by a rise in jejunal oleylethanolamide (OEA). Its level was higher in HPD-fed mice than in controls after saline infusion and was not changed by lipids. Overall, we demonstrate that lipid binding to intestinal CD36 is sufficient to produce a satiety effect. Moreover, it could participate in the satiety effect induced by HPD. Intestine can modulate FI by several mechanisms including an increase in OEA production and CD36 gene expression. Furthermore, intestine of mice adapted to HPD have a diminished capacity to modulate their food intake in response to dietary lipids

Chronic Consumption of Farmed Salmon Containing Persistent Organic Pollutants Causes Insulin Resistance and Obesity in Mice

Background: Dietary interventions are critical in the prevention of metabolic diseases. Yet, the effects of fatty fish consumption on type 2 diabetes remain unclear. The aim of this study was to investigate whether a diet containing farmed salmon prevents or contributes to insulin resistance in mice. Methodology/Principal Findings: Adult male C57BL/6J mice were fed control diet (C), a very high-fat diet without or with farmed Atlantic salmon fillet (VHF and VHF/S, respectively), and Western diet without or with farmed Atlantic salmon fillet (WD and WD/S, respectively). Other mice were fed VHF containing farmed salmon fillet with reduced concentrations of persistent organic pollutants (VHF/S-POPs). We assessed body weight gain, fat mass, insulin sensitivity, glucose tolerance, ex vivo muscle glucose uptake, performed histology and immunohistochemistry analysis, and investigated gene and protein expression. In comparison with animals fed VHF and WD, consumption of both VHF/S and WD/S exaggerated insulin resistance, visceral obesity, and glucose intolerance. In addition, the ability of insulin to stimulate Akt phosphorylation and muscle glucose uptake was impaired in mice fed farmed salmon. Relative to VHF/S-fed mice, animals fed VHF/S-POPs had less body burdens of POPs, accumulated less visceral fat, and had reduced mRNA levels of TNFa as well as macrophage infiltration in adipose tissue. VHF/S-POPs-fed mice further exhibited better insulin sensitivity and glucose tolerance than mice fed VHF/S. Conclusions/Significance: Our data indicate that intake of farmed salmon fillet contributes to several metabolic disorders linked to type 2 diabetes and obesity, and suggest a role of POPs in these deleterious effects. Overall, these findings may participate to improve nutritional strategies for the prevention and therapy of insulin resistance

Sex-specific metabolic alterations induced by environmental pollutants

International audienceDiabetes and obesity are the biggest public health challenge and the current prevalence of these chronic diseases has reached epidemic proportions worldwide. Apart from genetic alterations and lifestyle, exposure to environmental chemicals has emerged as a new cause of metabolic diseases. Notably, several compounds that mimic or oppose hormone activity defined as endocrine disruptors (EDs), may exert metabolic disturbances through interfering with the regulatory roles of the sex steroids (among other hormones) in energy homeostasis. However, most studies to date have investigated the metabolic impact of EDs on males and there is a lack of information regarding the metabolic impact of endocrine disruptors in females. There is as well a paucity of data for both sexes related to the metabolic impact resulting from the exposure to a mixture of EDs which is a more realistic scenario than the exposure to chemicals individually. Hopefully, conducting studies on both sexes in situations of multi-exposure to chemicals will help at better understanding the sex-biased mechanisms linked to endocrine disruption that could be helpful to improve and personalize treatments of diseases for which obesity is a risk factor, such as the metabolic syndrome and the hormono-dependent cancers

Life-long consumption of low-dosed food pollutants on metabolic health

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Environmental Pollutants and Metabolic Disorders: The Multi-Exposure Scenario of Life

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ManuscriptType: REVIEW ENDOCRINE DISRUPTING CHEMICALS IN MIXTURE AND OBESITY, DIABETES AND RELATED METABOLIC DISORDERS Number ID: 03051109 Running Title : Chemicals and Metabolic Disorders

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Presence of multiple functional polyadenylation signals in the 3′-untranslated region of human corticotropin receptor cDNA

AbstractWe present 2.59 kb of the 3′-non-coding region of the ACTH receptor cDNA that contains seven potential polyadenylation signals. Among these signals, five are functional as detected by 3′-RACE and are consistent with the transcripts of 1.8, 3.4 and 4 kb visualized on Northern blots. We propose that the most likely molecular mechanism for the multiple ACTH-R mRNA transcripts is the alternative use of polyadenylation signals